Elevated Levels of Plasma Mitochondrial DNA DAMPs Are Linked to Clinical Outcome in Severely Injured Human Subjects
Open accessAbstract
In Brief Objective: Our objective was to execute a prospective cohort study to determine relationships between plasma mtDNA DAMP levels and the occurrence of systemic inflammatory response syndrome (SIRS), multiple organ dysfunction syndrome (MODS), and mortality. Background: Mitochondrial DNA damage-associated molecular patterns (DAMPs) accumulate in the circulation after severe injury. Observations in animal models demonstrate that mtDNA DAMPs contribute to organ dysfunction; however, the link between plasma mtDNA DAMPs and outcome in severely injured human subjects has not been established. Methods: DNA was isolated from plasma samples taken from severely injured patients at hospital days 0, 1, and 2. Real-time PCR was used to quantify selected ≈200 base pair sequences of mtDNA within the COX1, ND1, and ND6 genes, as well as from the D-Loop transcriptional regulatory region. MODS was defined as a Denver Multiple Organ Failure score of 4 or greater. Results: MtDNA DAMPs were quantified as PCR threshold cycle number. Lower threshold cycles indicate increased mtDNA DAMP content. Patients with SIRS had significantly increased mtDNA DAMP levels in all 4 sequences examined (32.14 ± 0.90 vs 29.00 ± 1.15 for COX1, 31.90 ± 0.47 vs 30.16 ± 1.42 for ND1, 32.40 ± 0.61 vs 28.94 ± 1.13 for ND6, and 33.12 ± 0.83 vs 28.30 ± 1.14 for D-Loop). Patients who developed MODS also had elevated mtDNA DAMP levels compared with those who did not (32.57 ± 0.74 vs 27.12 ± 0.66 for COX1, 32.45 ± 0.65 vs 28.20 ± 0.73 for ND1, 32.52 ± 0.56 vs 27.60 ± 0.79 for ND6, and 32.85 ± 0.75 vs 27.86 ± 1.27 for D-Loop). Patients with above-median mtDNA DAMP levels had a significantly elevated relative risk for mortality. Four patients died secondary to severe MODS. Conclusions: These findings comprise the first observational evidence that plasma mtDNA DAMPs is associated with the evolution of SIRS, MODS, and mortality in severely injured human subjects. We executed a prospective cohort study to determine relationships between plasma levels of mtDNA damage-associated molecular patterns (DAMPs) and the occurrence of systemic inflammatory response syndrome (SIRS), multiple organ dysfunction syndrome (MODS), and mortality in severely injured human patients. Plasma mtDNA DAMPs, measured by quantitative real time polymerase chain reaction, were elevated in severely injured patients developing SIRS, MODS, and who died in comparison to severely injured subjects who did not develop complications and survived. These observations comprise the first observational evidence that plasma mtDNA DAMPs are linked to the evolution of SIRS, MODS, and mortality in severely injured human subjects.
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Extracellular mitochondria have been identified in damaged tissues, diverse inflammatory conditions, and in the blood of critical care patients.
“Extracellular mitochondria have been identified in damaged tissues (8, 18–20); diverse inflammatory conditions (11, 12, 14, 21–24); and in the blood of critical care patients (22).”
From Autoantibodies in Systemic Lupus Erythematosus Target Mitochondrial RNA (2019) · cites this paper as [23]
The Methods describe blood sampling from severely injured ICU patients, and the Discussion reports mitochondrial DNA DAMPs in their plasma. The paper measured mitochondrial DNA sequences, not intact extracellular mitochondria, so it supports the blood-and-patient setting but not the claimed identification of extracellular mitochondria. (LLM, conf=0.88)
Experimental — accuracy not yet measuredExtracellular mtDNA is associated with various pathologies, including trauma, burn injury, cancer, and rheumatoid arthritis.
“As extracellular mtDNA is reportedly associated with various pathologies, including trauma25,26, burn injury27, cancer28 and rheumatoid arthritis17,29”
From Anti-mitochondrial autoantibodies in systemic lupus erythematosus and their association with disease manifestations (2019) · cites this paper as [27]
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Cites
Bone, R. C., BALK, R. A., Cerra, F. B., Dellinger, R. P., Fein, A. M., Knaus, W. A., Schein, R. M. H., & Sibbald, W. J. (1992) · CHEST Journal · doi:10.1378/chest.101.6.1644 · Cited by 13,192 · see citing works
American College of Chest Physicians/Society of Critical Care Medicine Consensus Conference
(1992) · Critical Care Medicine · doi:10.1097/00003246-199206000-00025 · Cited by 5,091 · see citing works
Circulating mitochondrial DAMPs cause inflammatory responses to injury
Zhang, Q., Raoof, M., Chen, Y., Sumi, Y., Sursal, T., Junger, W., Brohi, K., Itagaki, K., & Hauser, C. J. (2010) · Nature · doi:10.1038/nature08780 · Cited by 3,812 · see citing works
Genomic responses in mouse models poorly mimic human inflammatory diseases
Seok, J., Warren, H. S., Cuenca, A. G., Mindrinos, M. N., Baker, H. V., Xu, W., Richards, D. R., McDonald-Smith, G. P., Gao, H., Hennessy, L., et al. (2013) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1222878110 · Cited by 3,005 · see citing works
Yakes, F. M., & Van Houten, B. (1997) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.94.2.514 · Cited by 1,854 · see citing works
A genomic storm in critically injured humans
Xiao, W., Mindrinos, M. N., Seok, J., Cuschieri, J., Cuenca, A. G., Gao, H., Hayden, D. L., Hennessy, L. V., Moore, E. E., Minei, J. P., et al. (2011) · The Journal of Experimental Medicine · doi:10.1084/jem.20111354 · Cited by 1,226 · see citing works
Emerging role of damage-associated molecular patterns derived from mitochondria in inflammation
Krysko, D. V., Agostinis, P., Krysko, O., Garg, A. D., Bachert, C., Lambrecht, B. N., & Vandenabeele, P. (2011) · Trends in Immunology · doi:10.1016/j.it.2011.01.005 · Cited by 680 · see citing works
Oxidative stress induces degradation of mitochondrial DNA
Shokolenko, I. N., Venediktova, N. I., Bochkareva, A., Wilson, G. L., & ALEXEYEV, M. F. (2009) · Nucleic Acids Research · doi:10.1093/nar/gkp100 · Cited by 556 · see citing works
Al‐Mehdi, A., Pastukh, V. M., Swiger, B. M., Reed, D., Patel, M., Bardwell, G. C., Pastukh, V. V., ALEXEYEV, M. F., & Gillespie, M. N. (2012) · Science Signaling · doi:10.1126/scisignal.2002712 · Cited by 386 · see citing works
Self-citationMITOCHONDRIAL DNA IS RELEASED BY SHOCK AND ACTIVATES NEUTROPHILS VIA P38 MAP KINASE
Zhang, Q., Itagaki, K., & Hauser, C. J. (2010) · Shock · doi:10.1097/shk.0b013e3181cd8c08 · Cited by 354 · see citing works
Cheng, G., Kong, R., Zhang, L., & Zhang, J. (2012) · British Journal of Pharmacology · doi:10.1111/j.1476-5381.2012.02025.x · Cited by 345 · see citing works
Sun, S., Sursal, T., Adibnia, Y., Zhao, C., Zheng, Y. Z., Li, H., Otterbein, L. E., Hauser, C. J., & Itagaki, K. (2013) · PLoS ONE · doi:10.1371/journal.pone.0059989 · Cited by 216 · see citing works
Fredriksson, K., Tjäder, I., Keller, P., Petrovič, N., Ahlman, B. H. J., Scheele, C. C., Wernerman, J., Timmons, J. A., & Rooyackers, O. (2008) · PLoS ONE · doi:10.1371/journal.pone.0003686 · Cited by 168 · see citing works
VALIDATION OF POSTINJURY MULTIPLE ORGAN FAILURE SCORES
Sauaia, A., Moore, E. E., Johnson, J. L., Ciesla, D. J., Biffl, W. L., & Banerjee, A. M. (2009) · Shock · doi:10.1097/shk.0b013e31818ba4c6 · Cited by 143 · see citing works
Zhou, Z., Daugherty, W. P., Sun, D., Levasseur, J. E., Altememi, N., Hamm, R. J., Rockswold, G. L., & Bullock, M. R. (2007) · Journal of neurosurgery · doi:10.3171/jns.2007.106.4.687 · Cited by 99 · see citing works
Garcı́a, N., & Chávez, E. (2007) · Life Sciences · doi:10.1016/j.lfs.2007.08.019 · Cited by 94 · see citing works
Sursal, T., Stearns-Kurosawa, D. J., Itagaki, K., Oh, S., Sun, S., Kurosawa, S., & Hauser, C. J. (2012) · Shock · doi:10.1097/shk.0b013e318276f4ca · Cited by 91 · see citing works
Dobson, A. W., Grishko, V. I., LeDoux, S. P., Kelley, M. R., Wilson, G. L., & Gillespie, M. N. (2002) · American Journal of Physiology-Lung Cellular and Molecular Physiology · doi:10.1152/ajplung.00443.2001 · Cited by 87 · see citing works
Self-citationGrishko, V. I., Solomon, M., Wilson, G. L., LeDoux, S. P., & Gillespie, M. N. (2001) · American Journal of Physiology-Lung Cellular and Molecular Physiology · doi:10.1152/ajplung.2001.280.6.l1300 · Cited by 83 · see citing works
Self-citationProtection of INS-1 cells from free fatty acid-induced apoptosis by targeting hOGG1 to mitochondria.
Rachek, L. I., Thornley, N. P., Grishko, V. I., LeDoux, S. P., & Wilson, G. L. (2006) · Diabetes · doi:10.2337/diabetes.55.04.06.db05-0865 · Cited by 81 · see citing works
Druzhyna, N., Hollensworth, S. B., Kelley, M. R., Wilson, G. L., & LeDoux, S. P. (2003) · Glia · doi:10.1002/glia.10230 · Cited by 75 · see citing works
Ruchko, M. V., Gorodnya, O. M., Zuleta, A., et al. (2010) · Free Radical Biology and Medicine · doi:10.1016/j.freeradbiomed.2010.10.692 · Cited by 60 · see citing works
Gillespie, M. N., Pastukh, V., Zhang, Ruchko, M. V., Gorodnya, O. M., Bardwell, & Tuder, R. M. (2011) · International Journal of COPD · doi:10.2147/copd.s15922 · Cited by 60 · see citing works
Self-citationRole of nitric oxide-induced mtDNA damage in mitochondrial dysfunction and apoptosis
Rachek, L. I., Grishko, V. I., LeDoux, S. P., & Wilson, G. L. (2005) · Free Radical Biology and Medicine · doi:10.1016/j.freeradbiomed.2005.09.028 · Cited by 60 · see citing works
Koczor, C. A., Shokolenko, I. N., Boyd, A. K., Balk, S. P., Wilson, G. L., & LeDoux, S. P. (2009) · Journal of Biological Chemistry · doi:10.1074/jbc.m109.036020 · Cited by 56 · see citing works
Weinbroum, A. A., Hochhauser, E., Rudick, V., Kluger, Y. S., Karchevski, E., Graf, E., & Vidne, B. A. (1999) · doi:10.1097/00005373-199910000-00013 · Cited by 56 · see citing works
Chouteau, J. M., Obiako, B. O., Gorodnya, O. M., Pastukh, V. M., Ruchko, M. V., Wright, A. J., Wilson, G. L., & Gillespie, M. N. (2011) · American Journal of Physiology-Lung Cellular and Molecular Physiology · doi:10.1152/ajplung.00210.2011 · Cited by 48 · see citing works
Self-citationHashizume, M., Mouner, M., Chouteau, J. M., et al. (2012) · American Journal of Physiology-Lung Cellular and Molecular Physiology · doi:10.1152/ajplung.00071.2012 · Cited by 41 · see citing works
Gill, R., Ruan, X., Menzel, C. L., Namkoong, S., Loughran, P., Hackam, D. J., & Billiar, T. R. (2010) · Shock · doi:10.1097/shk.0b013e3181eddcab · Cited by 39 · see citing works
Mitochondrial function in sepsis: Respiratory versus leg muscle
Fredriksson, K., & Rooyackers, O. (2007) · Critical Care Medicine · doi:10.1097/01.ccm.0000278048.00896.4b · Cited by 39 · see citing works
Pfeifer, R., Kobbe, P., Darwiche, S. S., Billiar, T. R., & Pape, H. (2010) · Journal of Orthopaedic Research® · doi:10.1002/jor.21214 · Cited by 35 · see citing works
Mitochondrial DNA Damage Mediates Hyperoxic Dysmorphogenesis in Rat Fetal Lung Explants
Gebb, S. A., DeCoux, A., Waggoner, A., Wilson, G. L., & Gillespie, M. N. (2012) · Neonatology · doi:10.1159/000342632 · Cited by 29 · see citing works
Self-citationMuscle mitochondrial activity increases rapidly after an endotoxin challenge in human volunteers
Fredriksson, K., Fläring, U., Guillet, C., et al. (2009) · Acta Anaesthesiologica Scandinavica · doi:10.1111/j.1399-6576.2008.01851.x · Cited by 28 · see citing works
Edmonds, R. D., Vodovotz, Y., Lagoa, C., et al. (2011) · Physiological Genomics · doi:10.1152/physiolgenomics.00020.2011 · Cited by 24 · see citing works
Koczor, C. A., Snyder, J. W., Shokolenko, I. N., et al. (2009) · Methods in molecular biology · doi:10.1007/978-1-59745-521-3_15 · Cited by 18 · see citing works
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Research works printed but not linked: 1
- [20]Chouteau J Gorodnya O Ruchko M Novel fusion protein constructs targeting DNA repair enzymes to mitochondria protect against pseudomonas aeruginosa-induced acute lung injury in intact rats [Abstracts, 2011 ATS International Conference]. Am J Resp Crit Care Med 2011 183 A3763
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Surgical trauma‐induced immunosuppression in cancer: Recent advances and the potential therapies
Tang, F., Tie, Y., Tu, C., & Wei, X. (2020) · Clinical and Translational Medicine · doi:10.1002/ctm2.24 · Cited by 206 · see citing works
Mitochondrial DNA neutrophil extracellular traps are formed after trauma and subsequent surgery
McIlroy, D. J., Jarnicki, A. G., Au, G. G., Lott, N., Smith, D. W., Hansbro, P. M., & Balogh, Z. J. (2014) · Journal of Critical Care · doi:10.1016/j.jcrc.2014.07.013 · Cited by 187 · see citing works
Forms of extracellular mitochondria and their impact in health
Miliotis, S., Nicolalde, B., Ortega, M., Yepez, J., & Caicedo, A. (2019) · Mitochondrion · doi:10.1016/j.mito.2019.02.002 · Cited by 138 · see citing works
Zhao, Z., Wang, M., Tian, Y., Hilton, T., Salsbery, B., Zhou, E. Z., Wu, X., Thiagarajan, P., Boilard, E., Li, M., et al. (2016) · Blood · doi:10.1182/blood-2015-12-688838 · Cited by 110 · see citing works
The role of mitochondria in rheumatic diseases
Becker, Y. L. C., Duvvuri, B., Fortin, P. R., Lood, C., & Boilard, E. (2022) · Nature Reviews Rheumatology · doi:10.1038/s41584-022-00834-z · Cited by 81 · see citing works
Marcoux, G., Magron, A., Sut, C., Laroche, A., Laradi, S., Hamzeh‐Cognasse, H., Allaeys, I., Cabon, O., Julien, A., Garraud, O., et al. (2019) · Transfusion · doi:10.1111/trf.15300 · Cited by 87 · see citing works
Becker, Y., Loignon, R.-C., Julien, A.-S., Marcoux, G., Allaeys, I., Lévesque, T., Rollet-Labelle, E., Benk-Fortin, H., Cloutier, N., Melki, I., et al. (2019) · Scientific Reports · doi:10.1038/s41598-019-40900-3 · Cited by 75 · see citing works
Marcoux, G., Duchez, A.-C., Rousseau, M., Lévesque, T., Boudreau, L. H., Thibault, L., & Boilard, E. (2017) · Platelets · doi:10.1080/09537104.2016.1218455 · Cited by 71 · see citing works
Yuzefovych, L. V., Pastukh, V. M., Ruchko, M. V., Simmons, J. D., Richards, W. O., & Rachek, L. I. (2019) · PLOS ONE · doi:10.1371/journal.pone.0222278 · Cited by 59 · see citing works
Self-citationAutoantibodies in Systemic Lupus Erythematosus Target Mitochondrial RNA
Becker, Y., Marcoux, G., Allaeys, I., Julien, A.-S., Loignon, R.-C., Benk-Fortin, H., Rollet-Labelle, E., Rauch, J., Fortin, P. R., & Boilard, E. (2019) · Frontiers in Immunology · doi:10.3389/fimmu.2019.01026 · Cited by 59 · see citing works
Mitochondrial DNA and Exercise: Implications for Health and Injuries in Sports
Zanini, G., De Gaetano, A., Selleri, V., Savino, G., Cossarizza, A., Pinti, M., Mattioli, A. V., & Nasi, M. (2021) · Cells · doi:10.3390/cells10102575 · Cited by 46 · see citing works
Plataki, M., Cho, S. J., Harris, R. M., Huang, H.-R., Yun, H. S., Schiffer, K. T., & Stout-Delgado, H. W. (2019) · Scientific Reports · doi:10.1038/s41598-018-37438-1 · Cited by 42 · see citing works
He, J., Lu, Y., Xia, H., Liang, Y., Wang, X., Bao, W., Yun, S., Ye, Y., Zheng, C., Liu, Z., et al. (2015) · PLOS ONE · doi:10.1371/journal.pone.0124469 · Cited by 20 · see citing works
- Authors
- Simmons, J. D., Lee, Y.-L., Mulekar, S., Kuck, J. L., Brevard, S. B., Gonzalez, R. P., Gillespie, M. N., & Richards, W. O.
- Affiliations
- University of South Alabama (US)
- Corresponding author
- Simmons, Jon D.
- Lee, Yann-Leei
- Brevard, Sidney B.
- Gonzalez, Richard P.
- Richards, William O.
- Venue
- Annals of Surgery
- Published
- 2013-10
- Volume
- 258
- Issue
- 4
- Pages
- 591-598
- ISSN
- 0003-4932 (ISSN-L)
- PMC
- PMC3935616
- OpenAlex
- W2093468893
- Cited by
- 259
- References
- 36
- Citations by year
- 2026: 16 · 2025: 15 · 2024: 11 · 2023: 19 · 2022: 24 · 2021: 19 · 2020: 18 · 2019: 30 · 2018: 26 · 2017: 28 · 2016: 19 · 2015: 22 · 2014: 11
- FWCI
- 7.77
- Type
- journal article
- Language
- en
- Open access
- green
- europepmc.org
- Locations
- Annals of Surgery (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Funders
- National Heart, Lung, and Blood Institute (T32HL076125, R01HL058234, R01HL113614)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Mitochondrial Function and Pathology
- Health Sciences › Medicine › Epidemiology › Sepsis Diagnosis and Treatment
- Life Sciences › Immunology and Microbiology › Immunology › Inflammation biomarkers and pathways
- Keywords
- severe injuries, systemic inflammatory response syndrome, multiple organ failure, mortality, mitochondrial COI, ND1, ND6, D-loop, critically ill patients, clinical outcome prediction, mitochondrial DNA damage, sepsis, trauma (physical injury), burns, hemorrhagic shock
- MeSH terms
- Adult, Aged, Aged, 80 and over, DNA, Mitochondrial, Female, Genetic Markers, Humans, Male, Middle Aged, Multiple Organ Failure, NADH Dehydrogenase, Prognosis, Prospective Studies, Wounds and Injuries, Cohort Studies, Biomarkers, Injury Severity Score, Systemic Inflammatory Response Syndrome, Cyclooxygenase 1, Real-Time Polymerase Chain Reaction
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